Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease

Abstract

In Alzheimer’s disease (AD), soluble tau accumulates and deposits as neurofibrillary tangles (NFTs). However, a precise toxic mechanism of tau is not well understood. We hypothesized that over-expression of wild-type tau down-regulates brain-derived neurotrophic factor (BDNF), a neurotrophic peptide essential for learning and memory. Two transgenic mouse models of human tau expression and human tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells were used to examine the effect of excess or pathologically modified wild-type human tau on BDNF expression. Both transgenic mouse models, with or without NFTs, as well as hTau40-SH-SY5Y cells significantly down-regulated BDNF mRNA compared to controls. Similarly, transgenic mice over-expressing amyloid-β significantly down-regulated BDNF expression. However, when crossed with tau knockout mice, the resulting animals exhibited BDNF levels that were not statistically different from wild-type mice. These results demonstrate that excess or pathologically modified wild-type human tau down-regulates BDNF and that neither a mutation in tau nor the presence of NFTs is required for toxicity. Moreover, our findings suggest that tau at least partially mediates amyloid-β-induced BDNF down-regulation. Therefore, AD treatments targeting Aβ alone may not be effective without considering the impact of tau pathology on neurotrophic pathways.

Effect ofBDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease

“…However, these models propose that it is tau that downregulates BDNF expression. 25 If the faster cognitive decline and neurodegeneration in Met66 carriers observed here were a consequence of greater downregulation of BDNF by tau, then increases in CSF tau should be equivalent in preclinical mutation carriers who are Met66 carriers and Val66 homozygotes. The specific association between Met66 and increasing CSF tau observed here suggests that increases in CSF tau were a consequence, rather than a cause, of reduced CNS BDNF in humans.…”

Differential Effects of Chronic Immunosuppression on Behavioral, Epigenetic and Alzheimer’s Disease-Associated Markers in 3xTg-AD Mice

“…Primers were designed using Primer3 software (http://bioinfo.ut.ee/primer3/) and ordered from IDT (Coralville, IA, USA). BDNF mRNA copy number in each sample was normalized to its βactin mRNA copy number [53,92]. The macroH2A variant of the canonical histone H2A is encoded by two genes that produce distinct proteins, H2afy (encodes mH2A1) and H2afy2 (encodes mH2A2).…”

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

“…Taken together, these results suggest that gain beyond baseline levels of BDNF and PSD95 may serve to increase the synaptic strength of neurons, thereby contributing to the rescue of cognitive deficits. In contrast, reduced BDNF levels in APP23 mice were rescued when these mice were crossed with tau knockout mice (Rosa et al., 2016). In contrast, while mice expressing mutant APP show reductions in PSD95 and synaptophysin levels (Oakley et al., 2006), it remains to be established whether knocking down tau rescues these changes.…”